PROJECT SUMMARY Pancreatic cancer will be diagnosed in approximately 55,000 people in the U.S. in 2019. Nearly all of these patients will die from this disease because of the late stage at diagnosis and the ineffectiveness of current systemic therapies. The shortcomings of current diagnostic and therapeutic strategies is exemplified by the fact that even when patients are diagnosed prior to the development of identifiable metastatic disease (<15% of patients) and are treated with operative resection and adjuvant systemic therapy, the probability of five-year survival is approximately 10%. There is an urgent need for novel strategies to improve patient outcomes for this disease. Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are cystic tumors that represent the only radiographically identifiable precursor lesion of pancreatic cancer. IPMN is a ?whole-gland? process, and it is known that patients who undergo partial pancreatectomy for IPMN have an increased risk of developing cancer in the pancreatic remnant. Because of this, recommendations for patients who have undergone partial pancreatectomy for non-invasive IPMN is serial radiographic and/or endoscopic surveillance of their pancreatic remnant. Recent data from our group has shown that approximately 25% of patients will develop radiographic signs of IPMN progression within three to four years of resection. Between our four centers (Duke University Hospital, Johns Hopkins University Hospital, Massachusetts General Hospital, Memorial Sloan Kettering) we are currently following over 450 patients who have undergone resection for IPMN. These patients are ideally suited for a chemoprevention trial. The goal of this multi-institutional research effort is to perform the first-in-human chemoprevention trial for pancreatic adenocarcinoma. Patients who have undergone partial pancreatectomy, and have been found to have high-risk IPMN, will be eligible for this randomized double-blind placebo controlled Phase II trial (100 patients/arm). This trial will utilize the selective COX inhibitor sulindac, which has been demonstrated to be highly effective in preventing progression to pancreatic cancer in pre-clinical models. Clinical data from our group and others have demonstrated a strong association between inflammation and progression in patients with IPMN, and sulindac has been shown to decrease the size of IPMN in patients with these cystic precursor lesions. The primary endpoint will be the rate of radiographic progression after three years. Patients will be closely monitored, with alternating CT imaging and endoscopic ultrasound/fluid aspiration every six months. Secondary endpoints will include: (1) assessment of the effects of this treatment on cyst fluid inflammatory markers, and a previously developed cyst fluid biomarker panel, and (2) a novel approach to radiographic assessment (radiomics) for early detection of progression to malignancy.